Bone turnover has been implicated as a factor that may influence bone biomechanics and fracture incidence independently of overall amounts of bone mass. Anti-resorptive therapies reduce the overall amount of bone turnover, but recent findings suggest that there are differences in biomechanical effects among anti-resorptive treatments that cannot be explained by bone mass and/or total amount of bone remodeling. A commonly cited mechanism for the effects of bone turnover on bone quality is the ability of cavities formed during bone remodeling to disconnect structural elements or act as local stress concentrations. Both of these mechanisms can be sensitive to the number and size of individual remodeling events. The number and size of remodeling events and their effect on cancellous bone biomechanics are poorly understood because the features cannot be measured using existing techniques. In the proposed work we develop image processing and three-dimensional dynamic histomorphometry techniques capable of measuring remodeling event number and size as well as traditional dynamic histomorphometry measurements. The HYPOTHESIS is that bisphosphonates and selective estrogen receptor molecules regulate remodeling cavity number and size differently, resulting in divergent biomechanical effects of these two classes of anti-resorptive therapy that cannot be explained by bone mass and/or overall amounts of bone turnover. Specific Aims: (1) Implement an automated three-dimensional dynamic bone histomorphometry technique capable of achieving measures of basic multicellular unit number, depth and surface size as well as three-dimensional versions of traditional histomorphometry indices. (2) Utilize these techniques in a rat model of estrogen depletion to test the idea that a bisphosphonate (risedronte) and a selective estrogen receptor molecule (raloxifene) have different effects on the number or size of remodeling events independent of total bone volume or bone turnover. Determine if remodeling event number or size are related to bone biomechanics using finite element modeling techniques. Clinical Significance: This project will provide more comprehensive methods of relating bone cell activity to cancellous bone structure and biomechanics. Improved understanding of the local effects of osteoporosis interventions and pathologies on bone structure has the potential to lead to improved management of osteoporosis by providing more precise comparisons of treatments and the processes through which bone loss occurs. [unreadable] [unreadable] [unreadable]